International Journal of Psychiatry in Clinical Practice

ISSN: 1365-1501 (Print) 1471-1788 (Online) Journal homepage: http://www.tandfonline.com/loi/ijpc20

Silexan does not cause withdrawal symptoms even

when abruptly discontinued

M. Gastpar, W. E. Müller, H. P. Volz, H. J. Möller, S. Schläfke, A. Dienel & S.

Kasper

To cite this article: M. Gastpar, W. E. Müller, H. P. Volz, H. J. Möller, S. Schläfke, A. Dienel & S.
Kasper (2017): Silexan does not cause withdrawal symptoms even when abruptly discontinued,
International Journal of Psychiatry in Clinical Practice, DOI: 10.1080/13651501.2017.1301488

To link to this article: http://dx.doi.org/10.1080/13651501.2017.1301488

Published online: 20 Mar 2017.

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INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE, 2017
http://dx.doi.org/10.1080/13651501.2017.1301488

ORIGINAL ARTICLE

Silexan does not cause withdrawal symptoms even when abruptly discontinued
€llerd, S. Schl€afkee, A. Dienele and S. Kasperf
€llerb, H. P. Volzc, H. J. Mo
M. Gastpara, W. E. Mu
a
Fliedner Klinik Berlin, Berlin, Germany; bDepartment of Pharmacology, Biocenter Goethe-University, Frankfurt, Germany; cHospital for
Psychiatry, Psychotherapy and Psychosomatic Medicine, Schloss Werneck, Werneck, Germany; dClinic for Psychiatry and Psychotherapy,
Ludwig Maximilians University, Munich, Germany; eDr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany; fDepartment of Psychiatry and
Psychotherapy, Medical University of Vienna, Vienna, Austria

ABSTRACT ARTICLE HISTORY

Objective: Subsequent to a randomised, double-blind, double dummy clinical trial assessing the efficacy Received 22 February 2017
of silexan compared to placebo and paroxetine in patients suffering from generalised anxiety disorder Accepted 27 February 2017
(GAD), a 1week follow-up phase was added in order to assess possible withdrawal symptoms of silexan
after abrupt discontinuation.
KEYWORDS
Methods: Participants received silexan 80 mg/d, silexan 160 mg/d, paroxetine 20 mg/d, or placebo at a Discontinuation effects;
ratio of 1:1:1:1. Study medication was discontinued after the 10 week active treatment phase of the ori- GAD; lavender oil; PWC-20;
ginal trial. Whereas paroxetine was tapered as indicated, silexan administration was discontinued abruptly. silexan
Assessment of possible withdrawal effects was done using the Physician Withdrawal Checklist question-
naire (PWC-20).
Results: During the 1 week down-titration phase, mean total PWC-20 scores had reduced by 0.19 in pla-
cebo, 0.23 in silexan 80, 0.65 in silexan 160, and 0.51 in paroxetine. The median change in all four groups
was 0.00. In none of the treatment groups withdrawal effects occurred after discontinuation.
Conclusions: Values assessed for the silexan groups indicate the absence of a dependency potential of
this preparation.

Objective
Given the fact that anxiety disorders belong to the most com-
mon illnesses in Western civilisation, the demand for efficacious
and safe anxiolytics is existent and constantly growing (Carter
et al. 2001; Rickels et al. 2008). Despite their popularity, the dis-
continuation of many pharmacological agents is often problem-
atic as it is associated with characteristic, sometimes severe,
withdrawal symptoms including anxiety, insomnia, restlessness,
poor concentration, and muscle aches (Baldwin et al. 2007).
Benzodiazepines harbour considerable dependency risks that
sometimes even overweigh beneficial effects and thus have to
be tapered off, often with medicinal/psychological assistance, in
order to prevent or at least to minimise the degree of these
symptoms. Abrupt withdrawal of these agents is often subject to
possibly serious adverse events, sometimes only short-term pre-
scription is recommended. (Lader et al. 2009). Even selective
serotonin reuptake inhibitors (SSRIs) are subject of discontinu-
ation syndrome and need a tapering off at the end of treatment
(Tamam & Ozpoyraz 2002).
With the anxiolytic efficacy of silexan, a patented active sub-
stance with an essential oil produced from Lavandula angustifo-
lia flowers, increasingly coming into focus of recent research
(Kasper et al. 2014), also the safety of this drug is of growing
interest. In this study, possible withdrawal symptoms of the lav-
ender oil preparation silexan in patients suffering from general-
ised anxiety disorder (GAD) were assessed and analysed in order
to evaluate the safety of the preparation.
Methods
The potential of silexan1 to cause withdrawal symptoms after
abrupt discontinuation was investigated. For this purpose, findings
from a follow-up phase of a clinical trial assessing the efficacy of
silexan compared to placebo and paroxetine in patients suffering
from GAD (Kasper et al. 2014) were documented and analysed.
The original study as well as the follow-up phase were designed
as a randomised, double-blind, double-dummy trial. Five hundred
and thirty nine adults with GAD were included, randomised, and
treated between May 2007 and November 2010. Eligible patients
received either one of two different doses of silexan, paroxetine,
or placebo. Paroxetine, which is a drug of the SSRI type, was
chosen as an active control as it is considered one of the first-line
therapy options in many psychiatric disorders and well-established
in GAD treatment (Bandelow et al. 2012).
The original trial advised a 10 week treatment duration. During
this phase, patients were administered silexan 80 mg/d, silexan
160 mg/d, paroxetine 20 mg/d, or placebo at a ratio of 1:1:1:1
according to randomisation. Medication was contained in capsules
for each of which identically matched placebo capsules were
available.
After the active treatment there was a 1week down-titration
phase introduced for the withdrawal of paroxetine, during which
the discontinuation effects presented here were documented.
During the down-titration phase (week 11), participants received
study medication according to randomisation every other day.
Whereas the paroxetine group kept taking 20 mg paroxetine

CONTACT Siegfried Kasper biol-psychiatry@meduniwien.ac.at Department of Psychiatry and Psychotherapy, Medical University of Vienna, W€ahringer G€
urtel
18-20, Vienna 1090, Austria
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
2 M. GASTPAR ET AL.

Figure 1. Physician withdrawal checklist (PWC-20).

16

14

12

10
PWC-20 total score

6
Placebo (n=105)
4 Silexan 80mg (n=115)

2 Silexan 160 mg (n=97)

tapered Paroxene*
0 (n=101)
week 10 week 11
Figure 2. Change of PWC-20 total score (mean ±95% confidence interval) during discontinuation (silexan discontinued abruptly, paroxetine tapered).
After trial com-
pletion at end of week 10 patients randomised to paroxetine were administered paroxetine 20 mg every other day until end of week 11 in order to appropriately
down-titrate medication.

capsules, participants randomised to one of the silexan groups
or to the placebo group were given capsules containing
placebo, thus inducing an abrupt discontinuation of silexan
administration.
Discontinuation symptoms were assessed using the 20-item
Physician Withdrawal Checklist (PWC-20, Figure 1). The PWC-20
was originally developed to detect benzodiazepine-like withdrawal
symptoms caused by anxiolytics of the NON-SSRI type (Rickels
et al. 2008). After a minimum treatment duration of 56 d, partici-
pants had to provide a valid data set derived from PWC-20 filled
out at the end of week 10 (end of active treatment) and at the
end of week 11 (end of trial). Withdrawal effects are indicated by
an increase in the total score of PWC-20 after discontinuation of a
treatment. Discontinuation effects were measured by assessing
the change in the total PWC-20 scores (Figure 2).
Results
Withdrawal symptoms of 97 patients treated with 160 mg/d
silexan, 115 patients treated with 80 mg/d silexan, 101 patients
treated with 20 mg/d paroxetine, and 105 patients treated with
placebo could be analysed. All patients had been treated for at
least 56 d. Symptoms assessed by the PWC-20 after the active
treatment phase (end of week 10) were more frequent and more
severe in the placebo group than in the others, resulting in high-
est scores in this group. At the end of the active treatment mean
 INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 3

Table 1. Physician withdrawal checklist (PWC-20) values after 10 weeks of treatment (week 10) and change after down-titration phase
(week 11 to week 10) (mean ± SD).
Placebo (N ¼ 105) Silexan 80 mg (N ¼ 115) Silexan 160 mg (N ¼ 97) Paroxetine 20 mg (N ¼ 101)
Total score
Week 10 11.43 ± 10.79 7.53 ± 7.41 6.65 ± 9.67 8.80 ± 7.87
Week 11 to Week 10 0.19 ± 4.20 0.23 ± 3.81 0.65 ± 4.93 0.51 ± 4.47
Total number of symptoms
Week 10 7.57 ± 5.61 5.61 ± 4.32 4.68 ± 5.16 6.50 ± 5.02
Week 11 to Week 10 0.31 ± 2.47 0.40 ± 2.62 0.25 ± 2.84 0.55 ± 2.60

total scores were 11.43 ± 10.79 in the placebo group, 7.53 ± 7.41 in  Besides its proven efficacy in GAD treatment, silexan was
the silexan 80 group, 6.65 ± 9.67 in the silexan 160 group, and shown to harbour no dependency potential, thus being a
8.80 ± 7.87 in the paroxetine group. At the end of the trial (end of safe therapy option that does not require tapering after
week 11), mean total scores had reduced by 0.19 ± 4.20 in the pla- termination of treatment.
cebo group, 0.23 ± 3.81 in the silexan 80 group, 0.65 ± 4.93 in the
silexan 160 group, and 0.51 ± 4.47 in the paroxetine group. The Note
median change of total PWC-20 scores was 0.00 in all four groups
1. SilexanV (WSV 1265) is the active substance of LaseaV (Dr.
R R R

(Table 1).
Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany).

Discussion Acknowledgements
Since the anxiolytic efficacy of both silexan and paroxetine is
The sponsor of the study was Dr. Willmar Schwabe GmbH & Co.
superior to that of placebo (Kasper et al. 2014), some of the symp-
KG. Medical writing by Christine Weidl.
toms assessed by the PWC-20 like anxiety/nervousness and rest-
lessness/agitation were treated by these active medications,
whereas primary disease symptoms of participants who received Disclosure statement
placebo remained untreated, thus resulting in inter-group differ-
Siegfried Kasper received grants/research support, consulting fees
ences in the total PWC-20 scores at the end of the active treat-
and/or honoraria within the last three years from Angelini, AOP
ment period (end of week 10).
Orphan Pharmaceuticals AG, AstraZeneca, Eli Lilly, Janssen, KRKA-
While tapering was done as indicated in paroxetine, silexan
Pharma, Lundbeck, Neuraxpharm, Pfizer, Pierre Fabre, Schwabe
was discontinued abruptly. Analysis of the PWC-20 assessment of
and Servier.
withdrawal effects indicates the absence of such effects in all four
M. Gastpar has served as member of advisory boards for
randomisation groups after discontinuation. In all four groups, the
Schwabe and Servier and on speaker’s bureaus of Servier and
average number of symptoms as well as the average total PWC-20
Schwabe.
score even reduced slightly during the one-week observation
Walter E. M€ uller received grant support from Schwabe and
phase following the active treatment. Differences between groups
UCB as well as speakers honorarium from Lundbeck,
regarding the degree of change in withdrawal effects after discon-
Neuraxpharm, and Schwabe.
tinuation could not be observed, with the median change in total
Hans-Peter Volz received consulting fees and/or honoraria for
scores being 0.00 in all four groups (Figure 2). The absence of a
lectures within the last 2 years from Lundbeck GmbH, Pfizer
dependency potential of the silexan preparation could thus be
Pharma GmbH, Otsuka Pharma GmbH, Dr. Willmar-Schwabe
shown.
GmbH & Co. KG, Bayer vital GmbH, Janssen-Cilag GmbH, neurax-
Despite the connection of paroxetine with discontinuation syn-
pharm GmbH, AstraZeneca GmbH, Lilly Deutschland GmbH,
drome (Tamam & Ozpoyraz 2002), withdrawal effects in patients
Servier Deutschland GmbH.
of the paroxetine group were comparable to those in the silexan
Hans-J€
urgen Möller received honoraria for lectures or for advis-
and placebo groups, which is likely to be due to the performance
ory activities in the last three years by the following pharmaceut-
of the necessary gradual down-titration of this medication.
ical companies: Lilly, Lundbeck, Servier, Schwabe and Bayer. He
was president or in the Executive Board of the following organisa-
Conclusions tions: CINP, ECNP, WFSBP, EPA and chairman of the WPA-section
on Pharmacopsychiatry.
The analysis of withdrawal symptoms shows that silexan obviously
A. Dienel and S. Schl€afke are employees of Dr Willmar Schwabe
does not lead to dependency and, therefore, can safely be
GmbH & Co. KG.
discontinued without down-titration even after long-term
treatment. Given the proven efficacy of silexan in anxiety disor-
Funding
ders, this is an important finding further supporting the capability
of the drug as a safe therapeutic option for the treatment of anx- The sponsor of the study was Dr. Wilmar Schwabe GmbH & Co.
iety disorders. KG. Medical writing by Christine Weidl.

Key points References

 Assessment of safe withdrawal of lavender oil preparation
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efficacy in GAD.
 Abrupt discontinuation of silexan after 10 week treatment
caused no withdrawal effects in GAD patients.
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Discontinuation symptoms in depression and anxiety disorders.
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Bandelow B, Sher L, Bunevicius R, Hollander E, Kasper S, Zohar J,
Mo€ller HJ WFSBP Task Force on Mental Disorders in Primary
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